Large Amino Acid Transporter 1 Selective Liposomes of L-DOPA Functionalized Amphiphile for Combating Glioblastoma
Large Amino Acid Transporter 1 Selective Liposomes of L-DOPA Functionalized Amphiphile for Combating Glioblastoma
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DOI：
10.1021/acs.molpharmaceut.7b00569
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Chaudhuri, Arabinda
中科院分区：
文献类型：
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作者：
Bhunia, Sukanya;Vangala, Venugopal;Chaudhuri, Arabinda
尽管神经外科和放射治疗在过去十年中取得了显著进展，但胶质母细胞瘤患者的总体生存时间(OS)仍然不到两年。药物通过血脑屏障(BBB)的传输能力差，从而导致药物在胶质瘤组织中的积聚不佳，这极大地限制了全身化疗的范围。为此，在脑毛细血管内皮细胞(BCECs)和胶质瘤细胞上过表达的大氨基酸转运体-1(LAT1)已经开始使用。先前关于使用LAT1介导的模型药物输送的报告显示，它们的大脑蓄积。然而，旨在检测LAT1介导的有效化疗药物对脑肿瘤组织的治疗潜力的体内深入的胶质母细胞瘤回归研究尚未进行。本文报道了一种新型的L-3，4-二羟基苯丙氨酸功能化两亲物(L-多巴)制备的纳米级(100-135 nm)选择性脂质体载药载体的研究进展。用Rh-PE标记的Amphi-DOPA脂质体在未经处理的胶质瘤细胞(GL261)和预先与LAT1抗体孵育的GL261细胞中的体外研究表明，LAT1介导了细胞摄取。在荷胶质母细胞瘤的小鼠体内，静脉注射近红外染料标记的双酚A脂质体，显示该染料在脑组织中优先蓄积。值得注意的是，静脉注射WP1066脂质体的Amphi-DOPA提高了CS7BL/6J小鼠原位建立的小鼠胶质母细胞瘤的总体存活率，与未治疗的小鼠组相比，提高了60%。此外，我们发现，当目前描述的LAT1介导的靶向化疗与体内使用Survivin(一种胶质母细胞瘤抗原)编码的DNA疫苗的DC靶向DNA疫苗相结合时，已建立的胶质母细胞瘤荷瘤小鼠的OS可以显著提高(与未经治疗的鼠组相比，提高了300%)。本研究结果为LAT1介导的胶质母细胞瘤全身化疗开辟了新的途径。
Despite significant progress in neurosurgery and radiation therapy during the past decade, overall survivability (OS) of glioblastoma patients continues to be less than 2 years. The scope of systemic chemotherapy is greatly limited by poor drug transport across the blood brain barrier (BBB) and, thereby, suboptimal drug accumulation in glioma tissue. To this end, use of large amino acid transporter-1 (LAT1) overexpressed both on brain capillary endothelial cells (BCECs) and glioma cells has begun. Prior reports on the use of LAT1 mediated delivery of model drugs showed their brain accumulations. However, in depth in vivo glioblastoma regression studies aimed at examining the therapeutic potential of LAT1 mediated delivery of potent chemotherapeutics to brain tumor tissues have not yet been undertaken. Herein, we report on the development of a nanometric (100-135 nm) promising LAT1 selective liposomal drug carrier prepared from a novel L-3,4-dihydroxyphenylalanine (L-DOPA) functionalized amphiphile (Amphi-DOPA). In vitro studies using Rh-PE labeled liposomes of Amphi-DOPA both in untreated glioma (GL261) cells and in GL261cells preincubated with LAT1 antibody revealed LAT1 mediated cellular uptake. Intravenously administered NIR-dye labeled liposomes of Amphi-DOPA in glioblastoma-bearing mice showed preferential accumulation of the dye in brain tissue. Notably iv administration of WP1066-loaded liposomes of Amphi-DOPA enhanced the overall survivability of CS7BL/6J mice bearing orthotopically established mouse glioblastoma by similar to 60% compared to that for the untreated mouse group. Furthermore, we show that the OS of established glioblastoma-bearing mice can be significantly enhanced (by >300% compared to that for the untreated mouse group) when the presently described LAT1 mediated targeted chemotherapy with WP1066-loaded liposomes of Amphi-DOPA is combined with in vivo DC-targeted DNA vaccination using a survivin (a glioblastoma antigen) encoded DNA vaccine. The present findings open a new door for LAT1 mediated systemic chemotherapy of glioblastoma.